Preventing common hereditary disorders through time-separated twinning

1
Preventing common hereditary disorders through
time-separated twinning

• Alexander Tchourbanov1 and Levon Abrahamyan2

1 Beijing Institute of Genomics (BIG), Chinese
Academy of Sciences (CAS)
2 Nebraska Center for Virology, University of
Nebraska-Lincoln, USA
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Preventing Mendelian disorders

• Involves two components - Carrier Testing and
  Prenatal Diagnosis
• Test Accuracy is 98.8, Sensitivity is 94.9 and
  Specificity 99.99.
• There are 6,700 of them
• They affect 3-4 of children
• They cause 20-30 of infant deaths and
• 11 of pediatric hospital admissions

Bell CJ, Dinwiddie DL, Miller NA, Hateley SL,
Ganusova EE, Mudge J, Langley RJ, Zhang L, Lee
CC, Schilkey FD, Sheth V, Woodward JE, Peckham
HE, Schroth GP, Kim RW, Kingsmore SF Carrier
testing for severe childhood recessive diseases
by next-generation sequencing. Sci Transl Med
2011, 3(65)65ra4.
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Aneuploidy prevention at BGI
5
Complex diseases incidence growth

• In Finland Type 1 Diabetes 32-year relative
  increase was 338 among children 1-4 yo 17
• In China, 23.46 million people currently have
  Type 2 Diabetes, and this number is projected to
  increase to 42.30 million by 2030. Associated
  medical costs are predicted to rise from 26.0
  billion in 2007 to 47.2 billion in 2030 18
• Nearly 5 times as many people have Celiac Disease
  in US today than during the 1950s 19
• The incidence of Autism among US children has
  reached a staggering 1 (110 out of 10,000)
  20,21
• The incidence of Asthma alone has at least
  tripled over the past 25 years and affects more
  than 22 million people in US 22

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Autism prevalence in US is 1 in 88!
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Complex diseases - the last line of defense
Complex disease prevention
Mendelian disorder prevention
Aneuploidy prevention
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Hermann Joseph Muller

• American geneticist, educator, and Nobel
  laureate best known for his work on the
  physiological and genetic effects
  of radiation (X-ray mutagenesis)
• Worked in USSR (1933-1937) and openly criticized
  Trofim Lysenko (called him a charlatan)
• He believed that it was possible to guide the
  evolution of mankind and create a better
  allotment of positive qualities than would
  naturally occur

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Genetic load

• Humans, like all wild animals, are subject to
  continuous change associated with mutations
• Few mutations can lead to genetic improvements,
  most of the mutations are either neutral or
  deleterious
• Many non-lethal mutations, compromising different
  genes, accumulate over time and spread through
  breeding increasing genetic load of the human
  race the frequency of potentially lethal genes
  in the gene pool
• Purifying selection reduces the genetic load by
  eliminating unfit individuals before reproduction
• Normally, rate in which deleterious mutations
  occur equals to the rate in which they are
  eliminated from the genetic pool

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The rate of opportunistic mutations

• Recent estimation of mutation chance based on
  whole genome sequencing is 77 novel mutations
  per diploid genome per generation
• Approximately 3-6 of these mutations are
  deleterious
• There are 100 genuine loss of function variants
  in average human genome with 20 genes completely
  inactivated

Jared C. Roach et. al. Analysis of Genetic
Inheritance in a Family Quartet by Whole-Genome
Sequencing Science 2010, 328, 636-639 MacArthur
DG et.al. A systematic survey of
loss-of-function variants in human protein-coding
genes. Science 2012, 335(6070)823-828
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Fathers of advanced age

• Genetic load increases at the rate of 2 de novo
  mutations per year of father's age at the time of
  conception 24
• Epidemiological studies report significant
  correlation between paternal age and increased
  risk of
• autism 25
• schizophrenia 26
• bipolar disorder 27,28
• Higher overall mortality has been reported for
  children of elder fathers 29

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The mortality of the Australian human population
by agefor 1901-1910 and 1997-1999
Sexual selection still works, natural is blocked
Medical Hypotheses (2001) 57(5), 633-637 (2001)
Harcourt Publishers Ltd Medicine may be reducing
the human capacity to survive C. N. Stephan, M.
Henneberg
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The process of elimination
Survive and reproduce 84
Eliminated 16
295.7
322.7
Mean number of mutations
The process offsets damage from 3 deleterious de
novo mutations per generation
Crow JF The origins, patterns and implications
of human spontaneous mutation. Nature Reviews
Genetics 2000, 140-47
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Purifying selection at work
Generation 1
20 mortality due to dysgenic effects
Generation 2
20 mortality due to dysgenic effects
Generation 3
Birth rate should be high enough to sustain
increased mortality before reproductive age
associated with purifying selection
20 mortality due to dysgenic effects
Generation 4
240 years
20 mortality due to dysgenic effects
Generation 5
20 mortality due to dysgenic effects
Generation 6
20 mortality due to dysgenic effects
Generation 7
20 mortality due to dysgenic effects
Generation 8
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Taking credit from nature
Generation 1
Generation 2
Generation 3

Generation 4
240 years
Generation 5
Generation 6
Generation 7
2 km from epicenter in a single radiation dose
200 R (40 mortality wounded)
Generation 8
Muller HJ Our load of mutations. Am. J. Hum.
Genet. 1950, 2111-176
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A better way to survive
Generation 1
Generation 2
Generation 3

Generation 4
240 years
Generation 5
Generation 6
Strange as it seems, we can in that case both
eat our cake and have it HJ Muller, 1950
Generation 7
Generation 8
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Types of stem cells
http//en.wikipedia.org/wiki/Cell_potency
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Microsurgical splitting of human embryo
Illmensee K, Levanduski M, Vidali A, Husami N,
Goudas VT (2010). "Human embryo twinning with
applications in reproductive medicine". Fertil.
Steril. 93 (2) 4237
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Embryo twinning by blastocyst bisection
Mitalipov SM, Yeoman RR, Kuo HC, Wolf DP
Monozygotic twinning in rhesus monkeys by
manipulation of in vitro-derived embryos. Biology
of Reproduction 2002, 661449-1455.
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Cleavage-stage biopsy for PGD
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Time delayed twinning process
Fertilized egg
8-cell stage
3-cell stage
2-cell stage
Implant
6-cell stage
Cryoconserve (50 years)
4-cell stage
8-cell stage
3-cell stage
Implant
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Maximum storage duration

• There was a recent report on a live birth from a
  frozenthawed pronuclear stage embryo almost 20
  years after its cryopreservation
• Specimen of Silene stenophylla sucessfully grew
  and flowered after 31,800 years of conservation
  in permafrost
• Vitality of micro-organisms found in ice up to
  300,000 years old could be reliably
  re-established
• DNA half life is 1.1 million years, i.e. in this
  time period DNA gets chopped in half

http//www.fertstert.org/article/S0015-0282(10)024
70-2/abstract Bidle KD, Lee S, Marchant DR,
Falkowski PG Fossil genes and microbes in the
oldest ice on earth. PNAS 2007,
104(33)13455-13460. Yashina S, Gubin S,
Maksimovich S, Yashina A, Gakhova E, Gilichinsky
D Regeneration of whole fertile plants from
30,000-y-old fruit tissue buried in Siberian
permafrost. PNAS 2012, 1118386109v2-201118386.
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According to Ethics Committee of the American
Society of Reproductive Medicine

• Splitting one embryo into 2 or more embryos could
  serve the needs of infertile couples in several
  ways
• As long as a couple is fully informed of the risk
  of such an outcome, there would appear to be no
  major ethical objection

The Ethics Committee of the American Society of
Reproductive Medicine (ASRM) Embryo splitting
for infertility treatment. Fertil Steril 2004,
82256-257.
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Generation X
Generation Y
Generation Z
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Preventing complex disorders
Study Type Disease incidence MZ twins pairwise concordance Prevention odds
Diabetes type 2 Diabetes type 2 Diabetes type 2 Diabetes type 2 Diabetes type 2
1 2 4 7.67-13.5 76 83 85.3 3.75 5.29 6.12
Diabetes type 1 Diabetes type 1 Diabetes type 1 Diabetes type 1 Diabetes type 1
2 3 5 5-8 5 9 10 years old gt 10 years old 0.01-0.034 45 13 27.3 50 16.7 38 1.82 1.15 1.37 2.0 1.20 1.61
Cancer Cancer Cancer Cancer Cancer
11 Breast Colorectum Prostate 1.92 1.55 1.12 14 16 21 1.14 1.17 1.25
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Preventing complex disorders
Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder
12 13 14 0.1-1 92 91 82 12.37 11.0 5.5
Allergies Allergies Allergies Allergies Allergies
15 Peanut 0.4-0.6 64.3 2.79
16 Astma past year (lt 50 50) yo Hay fever (lt 50 50) yo Seasonal rhinoconjunctivitis (lt 50 50) yo Eczema (lt 50 50) yo Pets (lt 50 50) yo Pollen (lt 50 50) yo Dust (lt 50 50) yo Insect bites (lt 50 50) yo Cat IgE (lt 50 50) yo Grass IgE (lt 50 50) yo Der p 1 IgE (lt 50 50) yo 8 3 30 27 15 11 24 16 13 4 21 14 22 12 10 11 12 4 21 10 22 9 29 0 39 30 31 18 34 30 39 7 32 17 43 8 20 11 28 44 56 35 54 14 1.300.97 1.161.05 1.231.09 1.161.20 1.431.03 1.171.03 1.370.95 1.121.00 1.221.74 1.771.38 1.691.06
23 Celiac disease 0.75 71.4 3.47
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Immediate benefits

• Will facilitate sustainable social development
• Prevention of further accumulation of undesirable
  mutations (genetic load)
• Significant reduction in incidence of complex
  diseases and virtual eradication of simple
  Mendelian disorders
• Having isogenic stem cells of total potency in
  repository will facilitate regenerative medicine
  of the future

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Thanks!
Available online at http//prevmed.big.ac.cn
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